The PI is a board-certified endocrinologist who has spent the past six years studying receptors in the steroid/thyroid hormone receptor superfamily, and is committed to pursuing a career in academic medicine. In particular, he plans to study the mechanisms by which T3 affects thyroid hormone receptor (TR) monomer, homodimer, and TR/nuclear protein heterodimer binding to a wide range of thyroid hormone response elements (TREs) using electrophoretic mobility shift assay, non-denaturing protein gel electrophoresis and methylation interference analyses. This is specifically relevant since he recently showed that T3 causes dissociation of TR homodimers but not TR/nuclear protein heterodimers from TREs, suggesting that the latter species may be the transciptionally active receptor species in the presence of T3. He also plans to define the roles of the unliganded and liganded form of these receptor species in transcription by co-transfecting plasmids encoding wild type TRs, mutant TRs, and nuclear proteins, such as retinoid X receptor which heterodimerizes with TRs, as well as reporter plasmids containing various TREs, into cells lines that do not contain endogenous TRs. Additionally, he plans to study the effects of T3 on DNA-binding of mutant TRs from patients with generalized resistance to thyroid hormone resistance to thyroid hormone resistance (GRTH). He will examine the molecular mechanisms by which single amino acid substitutions in the ligand binding region of these receptors cause a dominant negative effect on wild-type receptors, and can cause variable phenotypes and tissues resistance in affected families. His preliminary studies of a mutant TR from a family with GRTH suggest that formation of mutant TR homodimers which do not dissociate from TREs in the presence of T3 and inactive unliganded mutant TR/nuclear protein heterodimers which also bind to TREs, may account for the dominant negative effect by this particular mutant TR. Research on the roles played by the various TR species in T3-mediated regulation of transcription will provide better understanding of the action of this important hormone in health and disease.